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Page 4 of 15 Wu et al. Hepatoma Res 2023;9:6 https://dx.doi.org/10.20517/2394-5079.2022.37

showed a longer time to progression (TTP) with 13.3 months vs. 8.4 months, respectively. However, median
[18]
survival times were not different . Further evolution of TARE has led to radiation lobectomy (RL) and
[18]
radiation segmentectomy (RS) for earlier-stage disease . Because surgical intervention is often limited by
insufficient future liver remnant (FLR), RL was developed as a means to apply neoadjuvant TARE to the
hepatic lobe containing the tumor, which causes atrophy but also causes hypertrophy in contralateral liver
parenchyma as a compensatory mechanism. This effectively increases FLR prior to hepatectomy and is safe
with a low incidence of post-hepatectomy liver failure . RS delivers high doses of Y to particular hepatic
[19]
90
segments to minimize the risk of damage to surrounding parenchyma. Results for TTP, median OS, and
survival probability were promising in early-stage HCC . Finally, HAIC infuses high levels of
[20]
chemotherapeutic agents, such as 5-fluorouracil (5-FU) and cisplatin, into the hepatic artery in hopes of
direct drug delivery to the tumor while reducing the risk of systemic effects. Historically, large studies and
randomized controlled trials were lacking in demonstrating the role of HAIC . However, given recent
[21]
developments, HAIC has been an effective and safe therapy for locally advanced HCC when compared to
sorafenib [22,23] .

As LRT is used more widely for bridging to transplant or palliative treatment for advanced HCC, it is
plagued by the risk of progression and recurrence due to the release of angiogenic factors and the risk of
liver injury with repeated treatments. Therefore, it becomes increasingly relevant to explore the adjunct of
systemic therapy with the hopes of increasing its efficacy and decreasing the risk of tumor recurrence.

SYSTEMIC THERAPIES
For patients with advanced HCC, systemic therapy remains the only option. Sorafenib was the first systemic
therapy recognized as the first-line agent for advanced HCC based on the SHARP and Asia-Pacific
trials [9,11] . Since then, other systemic therapeutic agents have shown survival benefits and even superiority,
such as atezolizumab plus bevacizumab.

Systemic therapies can be divided into two categories: molecularly targeted agents (MTAs) and
immunotherapy. The MTAs include multikinase inhibitors with antiproliferative and antiangiogenic
properties by inhibiting receptors, for instance, platelet-derived growth factor receptor (PDGFR) and
vascular endothelial growth factor receptor (VEGFR) -β tyrosine kinases. These agents include sorafenib,
[24]
lenvatinib, cabozantinib, and regorafenib . In phase III multicenter non-inferiority REFLECT trial, the
median survival for lenvatinib of 13.6 months showed non-inferiority to sorafenib as first-line treatment for
unresectable HCC. More importantly, secondary endpoints of the trial demonstrated a significant increase
in PFS by 3.7 months and TTP by 5.2 months in levatinib compared to sorafenib . Later on, regorafenib
[25]
was approved as a second-line treatment in Child-Pugh class A patients with HCC that progressed on
sorafenib based on the RESORCE study. This phase III trial showed an increase in median overall survival
by 2.8 months compared to the placebo . The standard dose of 160 mg was associated with an increase in
[26]
adverse events-related dose reduction, interruption, and permanent discontinuation; therefore, dose
personalization is recommended . Following results from the CELESTIAL trial, cabozantinib was
[27]
approved for patients with HCC who were given sorafenib in the past. Cabozantinib demonstrated a
significant improvement in median OS of 10.2 months compared to the placebo of 8.0 months. In addition,
the treatment of cabozantinib also resulted in improved median PFS and objective response rates. It is
important to note that the rate of high-grade adverse events was approximately twice that of the placebo
group .
[28]

Other MTAs are the monoclonal antibodies that inhibit the VEGF/VEGFR pathway. Such examples include
bevacizumab (anti-VEGF-A) and ramucirumab (anti-VEGFR2) . Ramucirumab was shown to improve
[24]